Human and mouse genetic evidence indicates that the Low density lipoprotein Receptor Protein (LRP), a Wnt co-receptor LRP-51,2, plays an important role in bone remodeling3-6. In addition, canonical Wnt proteins and activated β-catenin stimulate Alkaline Phosphatase (AP) activity of osteoblast-like cells3,7. However, the precise roles of the canonical Wnts and their antagonist Dickkopf (Dkk) molecules in the regulation of osteogenesis remain unclear. Dkk proteins are believed to function as negative regulators in osteogenesis. Dkk proteins are cysteine-rich secreted proteins that have been shown to be negative regulators of Wnt signaling. Four Dkk proteins have been identified in humans and are referred to as Dkk1, Dkk2, Dkk3 and Dkk4.
There is a correlation between LRP5 mutations and bone mass, based on human studies, thereby suggesting that LRP5 plays a critical role in the regulation of bone development3-6. This conclusion was confirmed by the study of mice in which the LRP-5 gene is disrupted, as well as in mice in which the high bone mass mutation of LRP5 was targeted to bone tissue8,9. Evidence also indicates that canonical Wnts are classified based on either their ability to stabilize β-catenin to activate LEF-1/TCF transcriptional activity10, or on their ability to stabilize β-catenin to stimulate AP activity of osteoblast-like cells3,7. Together, all these findings suggest the involvement of canonical Wnt signaling in the regulation of osteogenesis. However, the mechanisms by which the canonical Wnt proteins regulate osteogenesis remain unclear.
Human bone marrow contains hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs), among others. In vivo, stem cells have the characteristic of self-regeneration, allowing them to renew themselves indefinitely. This renewal feature has not always been found to occur when the cells are grown in vitro. MSCs differentiate into mesenchymal tissue lineages, such as osteoblasts, chondrocytes, adipocytes, and others, whereas HSCs serve as precursors for multiple cell lineages, including blood cells. Mononuclear precursor cells are derived from early hematopoietic stem cells, and osteoclasts form from the fusion of mononuclear precursor cells. Natural Killer T (NKT) cells, a subset of T lymphocytes, are also derived from hematopoietic stem cells. Upon stimulation through their T cell receptors (TCRs), NKT cells produce high levels of immunoregulatory cytokines, which in turn regulate immune responses, such as the suppression of autoimmunity, tumor rejection and tissue graft associated response.
MSCs, also known as marrow stromal cells, osteoprogenetor cells and osteoblast stem cells, serve as feeder layers that regulate the microenvironment for the maintenance, expansion or renewal of hematopoietic stem cells. Osteoblasts are stromal cells that have been shown to produce hematopoietic growth factors at their endosteal surfaces, thereby playing an important role in HSC development. It has been demonstrated that increasing the number of osteoblasts results in a boost in HSC populations.1*,2* 
Wnt3a, one of the canonical Wnts, has been shown to function in the direct regulation of stem cell growth, particularly hematopoietic stem cell growth. Wnt3a is involved in numerous developmental events, including the proliferation and self-renewal of stem cells.3*,4* Wnt3a also functions in the indirect regulation of hematopoietic stem cell lineage development through stromal cells. (Yamane, T. et al, Wnt Signaling Regulates Hemopoiesis Through Stromal Cells”) It has been demonstrated that exogenous Dickkopf-1 (Dkk-1), an antagonist of Wnt, increases the proliferation of cultured mesenchymal stem cells. When a Dkk1 antibody was added, the proliferation of cultured mesenchymal stem cells decreased. The same Dkk1 effect was also observed in cultured MG-63 osteosarcoma cells.5*,7* However, the in vivo and in vitro effects of the Dkk proteins on hematopoietic stem cells, NKT cells and other types of stem cells have been unknown. The present invention describes the effect of Dkk proteins on various stem cells.